Design of amidobenzimidazole STING receptor agonists with systemic activity

Joshi M. Ramanjulu (), G. Scott Pesiridis, Jingsong Yang, Nestor Concha, Robert Singhaus, Shu-Yun Zhang, Jean-Luc Tran, Patrick Moore, Stephanie Lehmann, H. Christian Eberl, Marcel Muelbaier, Jessica L. Schneck, Jim Clemens, Michael Adam, John Mehlmann, Joseph Romano, Angel Morales, James Kang, Lara Leister, Todd L. Graybill, Adam K. Charnley, Guosen Ye, Neysa Nevins, Kamelia Behnia, Amaya I. Wolf, Viera Kasparcova, Kelvin Nurse, Liping Wang, Ana C. Puhl, Yue Li, Michael Klein, Christopher B. Hopson, Jeffrey Guss, Marcus Bantscheff, Giovanna Bergamini, Michael A. Reilly, Yiqian Lian, Kevin J. Duffy, Jerry Adams, Kevin P. Foley, Peter J. Gough, Robert W. Marquis, James Smothers, Axel Hoos and John Bertin
Additional contact information
Joshi M. Ramanjulu: GlaxoSmithKline
G. Scott Pesiridis: GlaxoSmithKline
Jingsong Yang: GlaxoSmithKline
Nestor Concha: GlaxoSmithKline
Robert Singhaus: GlaxoSmithKline
Shu-Yun Zhang: GlaxoSmithKline
Jean-Luc Tran: GlaxoSmithKline
Patrick Moore: GlaxoSmithKline
Stephanie Lehmann: Cellzome, GlaxoSmithKline R&D
H. Christian Eberl: Cellzome, GlaxoSmithKline R&D
Marcel Muelbaier: Cellzome, GlaxoSmithKline R&D
Jessica L. Schneck: GlaxoSmithKline
Jim Clemens: GlaxoSmithKline
Michael Adam: GlaxoSmithKline
John Mehlmann: GlaxoSmithKline
Joseph Romano: GlaxoSmithKline
Angel Morales: GlaxoSmithKline
James Kang: GlaxoSmithKline
Lara Leister: GlaxoSmithKline
Todd L. Graybill: GlaxoSmithKline
Adam K. Charnley: GlaxoSmithKline
Guosen Ye: GlaxoSmithKline
Neysa Nevins: GlaxoSmithKline
Kamelia Behnia: GlaxoSmithKline
Amaya I. Wolf: GlaxoSmithKline
Viera Kasparcova: GlaxoSmithKline
Kelvin Nurse: GlaxoSmithKline
Liping Wang: GlaxoSmithKline
Ana C. Puhl: GlaxoSmithKline
Yue Li: GlaxoSmithKline
Michael Klein: GlaxoSmithKline
Christopher B. Hopson: GlaxoSmithKline
Jeffrey Guss: GlaxoSmithKline
Marcus Bantscheff: Cellzome, GlaxoSmithKline R&D
Giovanna Bergamini: Cellzome, GlaxoSmithKline R&D
Michael A. Reilly: GlaxoSmithKline
Yiqian Lian: GlaxoSmithKline
Kevin J. Duffy: GlaxoSmithKline
Jerry Adams: GlaxoSmithKline
Kevin P. Foley: GlaxoSmithKline
Peter J. Gough: GlaxoSmithKline
Robert W. Marquis: GlaxoSmithKline
James Smothers: GlaxoSmithKline
Axel Hoos: GlaxoSmithKline
John Bertin: GlaxoSmithKline

Nature, 2018, vol. 564, issue 7736, 439-443

Abstract: Abstract Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA1. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants2. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides that mimic the endogenous STING ligand cGAMP; these have progressed into clinical trials in patients with solid accessible tumours amenable to intratumoral delivery3. Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING and cellular function. Intravenous administration of a diABZI STING agonist to immunocompetent mice with established syngeneic colon tumours elicited strong anti-tumour activity, with complete and lasting regression of tumours. Our findings represent a milestone in the rapidly growing field of immune-modifying cancer therapies.

Keywords: Stimulator Of Interferon Genes (STING); STING Agonists; Amidobenzimidazole (ABZI); Cyclic Dinucleotides; Enhance Tumor Immunogenicity (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (6)

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DOI: 10.1038/s41586-018-0705-y

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